Project Summary COPD/emphysema, the fourth leading cause of death in the US, is a chronic inflammatory lung disorder usually triggered by long-term cigarette smoke exposure. Although many therapies reduce the symptoms of COPD, no interventions exist which arrest or reverse the extensive architectural and functional damage that punctuate the disorder. Thus, therapies which not only reduce inflammation but also promote alveolar repair (resident cell survival, regenerative matrix production) are ideally suited for COPD efficacy. Angiotensin receptor blockers fulfill this dual role. The scientific premise is anchored on findings that: 1) angiotensin receptor blockade reverses genetic emphysema and protects against cigarette smoke induced emphysema in animal models manifest in reduced inflammation, reduced alveolar cell apoptosis and improved matrix morphology and 2) supportive observational studies and a randomized double-blinded placebo controlled trial of the angiotensin receptor blocker (ARB) Losartan (LOS) conducted under an NIH SCCOR mechanism that showed reversal or stabilization of emphysema in a subset of treated patients with established disease over a one year time frame. Such findings have led to an NIH-sponsored multicenter study of LOS in a cohort of patients with established emphysema (LEEP Trial). These data importantly suggest an unanticipated alveolar protective and reparative mechanism attached to angiotensin receptor blockade. Studies show that the antagonism of TGF? signaling induced by cigarette smoke (CS) or genetic perturbation is a direct ARB- mediated protective mechanism in experimental emphysema. New preliminary data presented in current proposal implicate enhanced PPAR? signaling by ARBs as a parallel and potentially reinforcing mechanism (to TGF? antagonism) for protection against CS-induced lung injury. LOS metabolites EXP3174 (3174) and EXP3179 (3179) selectively activate AT1R-dependent and AT1R-independent cascades, respectively, in both cell and animal model systems. Whereas AT1R-dependent repair engages selective antagonism of TGF? signaling, AT1R-independent repair promotes PPAR? agonism and antiinflammatory signaling. Aim 1 studies delineate how LOS as a prototypical ARB attenuates CS-induced lung inflammation and injury and promotes alveolar repair via coordinated activation of PPAR? plus inhibition of TGF?. Aim 2 studies establish how ARBs, via AT1R-dependent and -independent mechanisms, inhibit TGF? cascades to modulate alveolar resident cell survival and airspace repair in setting of CS-induced lung injury. Aim 3 studies utilize blood samples from LEEP trial enrollees treated with LOS to 1) establish whether blood LOS and metabolite levels associate with TGF? and PPAR? pathway biomarkers and 2) identify CYP variants that associate with metabolite levels. The proposed aims use primary cell models, experimental murine models and clinical samples from patients with emphysema treated with LOS to clarify the strategy by which ARBs promote airspace regeneration and also identify mechanisms for LOS metabolite production and their utility as precision biomarkers.